Hydrouracil compounds and processes for their production



Patented Nov. 16, 1937 UNITED STATES PATENT OFFICE HYDROURACIL COMPOUNDSAND PROO- ESSES FOR THEIR PRODUCTION Otto Dalmer, Claus Diehl, andHartmann Pieper, Darmstadt, Germany, assignors to Merck & Co. Inc.,Rahway, N. J., a corporation of New Jersey No Drawing. ApplicationJanuary 3, 1934, Serial No. 705,130. In Germany January 3, 1933 24Claims.

This invention relates to new hydrouracil compounds and theirmanufacture and has for its main object to provide for new and usefulsoporifics or narcotics.

Soporifics consisting of or containing compounds of the heterocyclicseries with an amidelike structure are known. The most important ofthese compounds are the barbituric acids, substituted by two hydrocarbonresidues in the 5-position, and their derivatives obtained byN-alkylation. Also disubstituted hydantoin compounds have been employedas soporifics.

" We'have found a principally new class of soporifics in hydrouracilcompounds of the general formula V R4 R1 C N/ iii 235 R: C :'-N

g have from physical and pharmacological aspects certain advantages overthe products substituted only at the carbon atom.

, The new class of soporifics has representatives similar to thediethylbarbituric acid with respect to their soporific action, but witha greater therapeutic scope. Of still more importance for the newsoporifics is the fact that certain of them have a high solubility,which is a great advantage over soporifics of the barbituric acid groupand over most of the known soporifics. The 5.5-diethyl-l-methylhydrouracil for example has a solubility in water, whichis 12 times as high as the solubility of diethylbarbituric acid. Verygood pharmacological results are also obtained with5.5-diethyl-hydrour'acil and its derivative, obtained by methylsubstitution at the nitrogen atom 3 and with products having higherhydrocarbonresidues as substituents such as 5-ethyl-5- butylhydrouracil''and 5-ethyl-5-isoamylhydrouracil.

The new compounds belonging to the new class of soporifics are obtainedby first reacting esters or amides of p-aminopropionic acid, beingdisubstituted by hydrocarbon radicals in a-POSitiOH to the carboxylgroup and having at least one hydrogen atom in the amino and amidogroup, with derivatives of carbonic or cyanic acid. Ureido or urethanocompounds are thus obtained, which are converted by ring formation intothe respective hydrouracil derivatives by treatment with condensingagents. Especially suitable condensing agents are the alkali metalalcoholates, especially sodium ethylate. Also other condensing agentsusual for ring formation in the barbituric acid series, such as sodiumamide, may however be employed.

Also those methods leading to hydrouracil derivatives fromaminopropionic acid derivatives by one step are suitable for themanufacture of the new products. Thus for example are hydrouracilderivatives directly obtained by treating amides of fi-aminopropionicacid, disubstituted by hydrocarbon residues in oz-POSitiOIl to thecarboxyl group and having at least one hydrogen atom in the amino andamido group, with esters of carbonic acid in presence of condensingagents mentioned above. These reactions may be illustrated by thefollowing formula:

For the manufacture of the derivatives Obtained by methyl substitutionat nitrogen atom 3 is especially suitable the methyl amide offi-aminopropionic acid substituted by two hydrocarbon residues inu-position to the carboxyl group. The preferred ester of carbonic acidfor the reaction described is the ethyl ester, which may easily beobtained. 1

As already explained above there are two main ways to obtain hydrouracilderivatives from the derivatives ofaminopropionic acid. These ways goover the ureido compounds in one case and over the urethano compounds inthe other case.

In the first case esters of B-aminopropionic acid, disubstituted byhydrocarbon residues in u-position to the carboxyl group and having atleast one hydrogen atom in the amino group, are the starting materials,in which the amino group is converted into the ureido group according toKnown methods. The best known method for this purpose comprises theemployment of potassium or other cyanates (Berichte der DeutschenChemischen Gesellschaft, vol. 33 (1900), page 3418; Annalen der Chemie,vol. 327 (1903), page 366). Decompositions with urea, eventually inpresence of baryta water, and with guanidine are described in Berichteder Deutschen Chemischen Gesellschaft, vol. 39 (1906), page 2953, vol.41

(1908) pages 2953, 2974 and 2977. Other methods for the purpose inquestion are the reaction of carbamic acid chlorides with esters .of.amino acids (Annalen der Chemie, vol.'244 1888) page 34) and the oldmethod of Wurtz (c. r. vol. 32 (1851), page 414) for reacting aminocompounds with esters of isocyanic acid.

, The ureido compounds obtained are treated with condensing agents toeffect ring formation, thus obtaining the corresponding hydrouracilderivatives Starting materials especially suitable for the synthesisjust described are the substitution derivatives. of the ethyl ester ofaminopropionic acid. The preferred method to obtain their ureidocompounds is their treatment with cyanates. Suitable oyanates are thealkali metal cyanates, especially potassium cyanate, and the esters of'cyanio acid, such as methyl isocyanate.

.In the second-case amides of B-aminopropionic acid, disubstituted' byhydrocarbon residues in u-position .to the carboxyl group and having atleastone. hydrogen atom in the aminoandamido group, are the startingmaterials. Substituted methyl amides of aminopropionic acid are espe-.cially suitable starting materials. Their amino group is converted byknown methods into the urethano group, a treatment with chlorinatedesters of carbonic acid, such as the ethyl ester, being especiallysuitable for this purpose. By further treatment of the urethanocompounds with theabove described condensing agents ring formation takesplace,.thus obtaining the corresponding hydrouracil compounds.

R; C O NH 134 R Examples 1(1) 105 g. of the hydrochloride of the ethyl,

ester of fleamino-oz-diethylpropionic acid, obtainedby catalyticreduction of the ethyl ester of diethylcyanoacetic acid, are dissolvedin 0 ccm. of water and a solution of 41 g. of potassium cyanate in 100com. of water isadded. The mixture is heated to about 50 C. for someminutes. The ethyl ester of fl-ureido-adiethylpropionic acidprecipitates as a colorless oil, which soon solidifies bycrystallization. The ester melts at 105-106 C., is nearly insoluble inwater but easily soluble in most of the organic solvents.

.A solution of sodium ethylate, made from 12 g. sodium in 200 com. or".absolute ethyl alcohol, is added .to 108 g. of the above ureidocompound, which is easily dissolved. The solution solidifies on heatingit to about 70 C. yielding a white crystalline mass. The reaction isfinished by short heating under reflux. The alcohol is distilled off atreduced pressure and the remaining sodium salt of 5-diethyl-hydrouraci1is dissolved in water; the solution is neutralized with acid. The5-diethylhydrouracil, which precipitates, is

purified by recrystallization with alcohol. The condensation may also beeffected with the same good result by using a solution of sodium inother alcohols instead of sodium ethylate.

(2) 56.1 g. of the ethyl ester of c-methylamino-u-diethylpropionic acid,boiling at 94 C. under a pressure of 13 mm. Hg and obtained by partialmethylation of the ethyl ester ofp-aminoa-diethylpropionic acid, areexactly neutralized with a mixture of 25.2 com. of aqueous 37%hydrochloric acid and 150 com. of water and treated in the same manneras described in Example 1 with a solution of 25 g. of potassium cyanatein little water. The ureido ester obtained melts at 78 C.

46 g. of the ureido ester are boiled for about two hours and a halfunder reflux with a solution of 4.6 g. of sodium in 120 com. of alcohol.The mixture is cooled and neutralized with hydrochloric acid. Thealcohol is distilled off under reduced pressure, and the residue isdissolved in water and ether. On concentrating the etherical solution1-methyl-5-diethylhydrouracil precipitates in the form of colorlessprisms melting at 103, soluble in water and easily soluble in nearly allorganic solvents.

(3) 25 g. of the hydrochloride of the methylamide offi-amino-a-diethylpropionic acid, melting at 148 C. and obtained bycatalytic reduction of the methylamide of diethylcyanoacetic acid aredissolved in 100 ccm. of-water. 150 com. of ether are added and whileturbinating and cooling com. of 33% sodium hydroxide solution and 17 g.of theethyl ester of chloroformic acid are run into the mixture. Theether is separated and the solution is dried with potassium carbonate.After distilling'off a viscous water white syrupremains, consisting ofthe methylamide of c-carbethoxyamino-a-diethylpropionic acid, which isdissolved in com. of absolute alcohol. To the solution is added asolution of 2.9 g. of sodium in 50 com. of absolute alcohol,

the mixture being then boiled on a water bath under reflux for about twohours. The alcohol is distilled ofi at reduced pressure and ether anddiluted hydrochloric acid are added to the residue. On concentrating theetherical solution 3-methyl-5-diethylhydrouracil crystallizes out inthin colorless'needles, melting at 88, soluble in water and easilysoluble in nearly all organic solvents.

(4) 173 g. of the ethyl ester of e-amino-u-diethylpropionic acid aredissolved in one liter of ether. A solution of 58 g. of methylisocyanatein 500 (mm. of ether is dropped in while cooling. The reaction takesplace immediately with strong evolution of heat. On distilling ofi theether the ethyl ester of B-N'-methylureido-a-diethylpropionio'acidcrystallizes in the form of long rays, melting at 54 C. The yield isquantitative.

20 g. of the ureido ester are heated with a solution of 23 g. of sodiumin 400 com. of absolute alcohol for about three hours'in an autoclave toabout 110-115 C. The alcoholic solution is exactly neutralized withconcentrated hydrochloric acid and the alcohol is distilled ofi atreduced pressure. The residue is taken up with water'and ether. Onconcentrating the solution 3-methyl-5-diethylhydrouracil crystallizesout.

(5) Liquid ethylamide of e-amino-a-diethylpropionic acid is prepared inthe same manner as described in Example 3 from the ethylamide ofdiethylcyano-acetic acid, melting at 71 and obtained fromdiethylcyanoacetylchloride and aqueous solution of ethylamine.

172 g. of this amide are dissolved in 300 com. of ether and providedwith a lower layer of 45 g. of sodium hydroxide dissolved in water.While cooling and turbinating 110 g. of the ethyl ester of chloroformicacid are dropped in. The etherical solution is separated and the residueis dried with potassium carbonate, whereupon the ether is distilled oif.The viscous colorless residue is the ethyl amide ofp-carbethoxyamino-a-diethylpropicnic acid, which is for about 2 hoursboiled under reflux on a Water bath with a solution of 23 g. of sodiumin 400 com. of absolute alcohol. The alcohol is distilled ofi and theresidue is dis solved in ether and the necessary amount of hydrochloricacid. On concentrating the etherical solution 3 ethyl5-diethylhydrouracil crystallizes out in thick colorless prisms meltingat 74 C. I (6) 197 g. of the ethyl ester of ethyl-n -butylcyanoaceticacid, boiling at 123125 C. at 14 mm. Hg, are dissolved in 1000 ccm. ofalcohol; 100 com. of 37% hydrochloric acid are added. The mixture isshaken for about one hour with molecular hydrogen in presence ofplatinum oxide at 70-75 and at 40 atmospheres pressure. The alcohol isdistilled off, a small amount of non-hydrogenated ester is removed byextraction with ether and an excess of sodium hydroxide solution isadded to the aqueous extraction residue. The'ethyl ester offi-amino-a-ethyl -butylpropionic acid precippropionic acid soonprecipitates as oil which solidifies. The solid product melts at 111 C.

244 g. of that fl-ureidoester are boiled under reflux for about one hourwith a solution of 23 g. of sodium in 400 com. of alcohol. The alcoholis distilled off, water is added to the residue and the mixture isfaintly acidified with diluted hydrochloric acid.5-ethyl-5-butyl-hydrouracil precipitates and is recrystallized withalcohol. The product consists of very fine white needles, arranged inform of a snow flake, melting at 185, easily soluble in hot alcohol andslightly soluble in water, ether and most of the other organic solvents.

(7) 109 g. of the ethyl ester of ethylphenylcyanoacetic acid aredissolved in 800 com. of alcohol. 50 com. of 37% hydrochloric acid areadded and the mixture is hydrogenated in presence of platinum oxide atC. and 40 atmospheres pressure. After about 45 minutes hydrogenation thealcohol is distilled off, the residue dissolved in water and thesolution extracted with petrol ether to remove non-hydrogenated ester.On addition of sodium hydroxide to the aqueous extraction residue theethyl ester of p-amino-aethyl-a-phenylpropionic acid separates. Theester is taken up with ether and dried with potassium hydroxide. Afterevaporation of the ether the ester distills over at 150-151 (11 mm. Hg).The ester is converted into the ester ofB-methylamino-a-ethyl-a-phenylpropionic acid by cautious methylation,said product boiling at 154 (12 mm. Hg)

235 g. of said ester are exactly neutralized with 500 com. of twicenormal hydrochloric acid, a concentrated aqueous solution of g. ofpotassium cyanate is added and the mixture is heated to about 50 C. fora short time. ing ureidoester separates in form of an oil, which soonsolidifies. Melting point 106-107 C. By boiling the ester for about onehour with a solu tion of 23 g. of sodium in 400 com. of alcohol 1-methyl-5 -ethyl-5-pheny1hydrouracil is formed. The alcohol is distilledofi and the residue neutralized with diluted hydrochloric acid. Smallwhite crystals precipitate, melting at l.84=.5 after recrystallizationwith alcohol, difii'oultly soluble in water and ether and easily solublein warm alcohol.

(8) 174 g. of the methylamide of phenylcyanoacetic acid, obtained bydissolving the ethyl ester of phenylcyanoacetic acid in aqueous solutionof methylamine, and sucking oil? the methylamide crystallized after somehours and melting at 102 0., are dissolved in 400 com. of absolutealcohol and reacted in the usual manner with 115 g. of ethylbromide anda solution of 23 g. of sodium in 400 com. of absolute alcohol. Thealcohol is distilled off and the methylamide of ethylphenylcyanoaceticacid obtained is recrystallized with ether, yielding colorless needlesmelting at 73 C.

200 g. of this methylamide are dissolved in 2 l. of alcohol, com. of 37%hydrochloric acid are added and the mixture is treated with molecularhydrogen in presence of platinum oxide. When about the theoreticalamount of hydrogen is taken up hydrogenation is stopped and the alcoholdistilled off. The remaining syrupy hydrochloride of the methylamide cfB-amino-u-ethyl-a-phenylpropionic acid, containing only small amounts ofunreacted starting material, is decomposed with sodium hydroxidesolution and the free base obtained is dissolved in ether, the ethericalsolution being dried with potassium carbonate. methylamide formed byhydrogenation is precipitated as other insoluble sulfate from itssolution by addition of a solution of concentrated sulfuric acid in coldether and thus separated from the The correspond The non-hydrogenatedstarting material. The hydrochloride is easily soluble in ether andtherefore not suitable for the separation. The methylamide ofc-amino-a-ethyl-a-phenyl-propionic acid made from the sulfate is acolorless viscous oil. Yield 195 g. I

193 g. of this methylamide are dissolved in 250 com. of ether. Asolution of 20 g. of sodium hydroxide in 200 com. of water and 55 g. ofthe ethyl ester of chloroformic acid are added while cooling. The etheris separated, the solution dried with potassium carbonate and distilled.The methylamide of ,8-carbethoxyamino-a-ethyl-u-phenylpropionic acidremains as viscous colorless syrup. The yield is quantitative. Thissyrup is for about 2 hours boiled under reflux with a solution of 12g.of sodium in 250 com. of absolute alcohol. The alcohol is distilled offat reduced pressure and ether and diluted hydrochloric acid are added tothe residue. solution 3methyl-5ethyl-5-phenylhydrouraci1 crystallizesout in form of colorlessprisms, melting at 135 C.

(9) 28 g. of the amide of B-amino-a-diethylpropionic acid and 25 g. ofdiethylcarbonate are for about 2 hours boiled under reflux with asolution of 4.6 g. of sodium in 100 ccm. of absolute alcohol. Thealcohol is distilled off at reduced pressure and the residue is taken upwith Water, neutralized with diluted hydrochloric acid.5-diethylhydrouracil with the same properties as the product of Example1 is obtained in good yield by separating it from the solution.

(10) 31 g. of the methylamide of ,c-amino-adiethylpropionic acid and 25g. of diethyl carbonate are boiled under reflux for about 3 hours with asolution of 4.8 g. of sodium in 100 ccm. of absolute alcohol. Thealcohol is distilled ofi at reduced pressure; theresidue is dissolved inwater and ether and neutralized with diluted acid. On concentrating theetherical solution 3-methyl-5- diethylhydrouracil is obtained, the sameproduct as in Example 3.

(11) A solution of 43 g. of the ethyl ester offi-ureido-a-diethylpropionic acid in 500 ccm. of benzene is boiled forsome hours under reflux with 9 g. of finely powdered sodium amide. Thebenzene is distilled off, the residue taken up with water andneutralized with hydrochloric acid. The 5-diethylhydrouracil is suckedoff, its properties being the same as those of the product of Example 1.

We claim:-

1. A method for making compounds of the hydrouracil series whichconsists in treating salts of alkyl esters of fl-aminopropionic acid,disubstituted by lower alkyl radicals in a-pOSifti0l1 to the carbcxylgroup and having at least one hydrogen atom in the amino group, withalkali metal cyanates and treating the urei-do compounds thus obtainedwith alkaline condensing agents to obtain hydrouracil compounds by ringformation.

.2. A method for making compounds of the hydrouracil series whichconsists in treating salt of ethyl ester of c-aminopropionic acid,disubstituted by lower alkyl radicals in lit-position to the carboxylgroup and having at leastone hydrogen atom in the amino group, withalkali metal cyanates and treating the ureido compounds thus obtainedwith alkaline condensing agents to obtain hydrouracil compounds by ringformation.

3. A method for making compounds of the hydrouracil series whichconsists in treating salts of alkyl esters of p-aminopropionic acid,disubstituted by lower alkyl radicals in a-position to On concentratingthe etherical the carboxyl group and having at least one hydrogen atomin the amino group, with alkali metal cyanates and treating the ureidocompounds thusobtained with alkali metal alcoholates to obtainhydrouracil compounds by ring formation.

4. A method for making compounds of the hydrouracil series whichconsists in treating salts of ethyl ester of fi-aminopropionic acid,disubstituted by lower alkyl radicals in d-DQSitiOl] to the carboxylgroup and having at least one hydrogen atom in the amino group, withalkali metal cyanates and treating the ureido compounds thus obtainedwith alkali metal alcoholates to obtain hydrouracil compounds by ringformation.

5. A method for making compounds of the hydrouracil series whichconsists in treating salts of alkyl esters of p-aminopropionic acid,disubstituted by lower alkyl radicals in oc-DOSitiOl'l to the carboxylgroup and having at least one hydrogen atom in the amino group, withalkali metal cyanates and treating the ureido compounds thus obtainedwith sodium alcoholate to obtain hydrouracil compounds by ringformation.

6. A method for making 5.5-diethylhydrouracil which consists in treatingthe hydrochloride of the ethyl ester of a, a-diethyl-fl-aminopropicnicacid with potassium cyanate and converting the ethyl ester of 0c,a-diEthYl-fi-lllfildOPIO- pionic acid obtained into5.5-diethylhydrouracil by condensation with sodium ethylate ascondensing agent.

7. A method for making a compound from the hydrouracil series whichconsists in treating the hydrochloride of the ethyl ester of a,a-diethyl-cmethylaminopropionic acid with potassium cyanate andconverting the ureido compound obtained into5.5-diethy1-l-methylhydrouracil by condensation treatment with sodiumethylate.

8. A hydrouracil compound having the general formula in which R1 and R2are lower alkyl radicals, and R3 and R4 are selected from the groupconsisting of hydrogen and lower alkyl radicals.

9. A hydrouracil compound having the general formula in which R1 and R2are lower alkyl radicals, and R3 and R4 are selected from the groupconsisting of hydrogen and lower alkyl radicals, at least one of R3 andR4 being hydrogen.

10. A hydrouracil compound having the general formula in which R1, R2and R3 are lower alkyl radicals and R4 is hydrogen.

11. A hydrouracil compound having the general formula in which R1, R2and R4 are lower alkyl radicals and R3 is hydrogen.

12. 5.5-diethylhydrouracil, action.

13. 5.5 diethyl 3 methylhydrouracil having somniferic action.

14. 5.5 diethyl 1 methylhydrouracil having somniferic action.

15. The step of treating a substance selected from the group consistingof ureido derivatives of alkyl esters of fi-aminopropionic aciddi-substituted by lower alkyl radicals in a-POSitiOIl to the 'carboxylgroup, and having at least 1 hydrogen atom in the amino group; andurethano derivatives of amides of p-aminopropionic acid disubstituted bylower alkyl radicals in apOSitin to the carboxyl group and having atleast one hydrogen atom in the amino and amido groups, with alkalinecondensing agents to obtain hydrouracil compounds by ring formation.

16. A method for making a compound from the hydrouracil series whichcomprises treating the hydrochloride of the methyl amide ofpamino-a-diethyl propionic acid with the ethyl ester of chlorocarbonicacid, and converting the resulting methyl amide ofp-carbethoxy-aminoa-diethylpropionic acid into3-methyl-5-diethylhydrouracil by condensation with sodium alcoholate.

17. A method for making compounds of the hydrouracil series, whichcomprises treating amides of p-amino-propionic acid, disubstituted bylower alkyl radicals in a-position to the carboxyl group, and having atleast one hydrogen atom in the amino and amido groups, with esters ofchlorocarbonic acid, and treating the urethano compounds thus obtainedwith alkaline condensing agents to obtain hydrouracil compounds byhaving somniferic ring formation.

18. A method for making compounds of the hydrouracil series whichcomprises treating amides of p-aminopropionic acid disubstituted bylower alkyl radicals in a-position to the carboxyl group, and having atleast one hydrogen atom in the amino and amido groups, with ethyl estersof chlorocarbonic acid, and treating the urethano compounds thusobtained by ring formation.

19; A method for making compounds of the hydrouracil series, whichcomprises treating amides of p-aminopropionicacid, disubstituted bylower alkyl radicals in a-DOSitiOD to the carboxyl group, and having atleast one hydrogen atom in the amino group, with esters ofchlorocarbonic acid, and treating the urethano compounds thus obtainedwith alkaline condensing agents to obtain hydrouracil compounds by ringformation.

20. A method for making compounds of the hydrouracil series, whichcomprises treating amides of B-amino-propionic acid, disubstituted bylower alkyl radicals in a-position to the carboxyl group, and having atleast one hydrogen atom in the amino and amido groups, with esters ofchlorocarbonic acid, and treating the urethano compounds thus obtainedwith an alkali metal alcoholate to obtain hydrouracil compounds by ringformation.

21. A method for making compounds of the hydrouracil series, whichcomprises treating amides of p-amino-propionic acid, disubstituted bylower alkyl radicals in u-DOSitiOIl to the carboxyl group, and having atleast one hydrogen atom in the amino and amido groups, with esters ofchlorocarbonic acid, and treating the urethano compounds thus obtainedwith sodium ethylate to obtain hydrouracil compounds by ring formation.

22. A method for making compounds of the hydrouracil series whichcomprises treating methyl amides of fi-aminopropionic acid disubstitutedby lower alkyl radicals in a-position to the carboxyl group, and havingat least one hydrogen atom in the amino and amido groups, with esters ofchlorocarbonic acid, and treating the urethano compounds thus obtainedwith alkaline condensing agents to obtain hydrouracil compounds by ringformation.

23. A method for making compounds of the hydrouracil series whichcomprises treating methyl amides of p-aminopropionic acid disubstitutedby lower alkyl radicals in a-position to the carboxyl group, and havingat least one hydrogen in the amino group, with ethyl esters ofchlorocarbonic acid, and treating the urethano compounds thus obtainedwith alkaline condensing agents to obtain hydrouracil compounds by thering formation.

24. A method for making compounds of the hydrouracil series whichcomprises treating methyl amides of ,B-aminopropionic acid disubstitutedby lower alkyl radicals in a-position to the carboxyl group, and havingat least one hydrogen in the amino group, with ethyl esters ofchlorocarbonic acid, and treating the urethano compounds thus obtainedwith sodium ethylate to obtain hydrouracil compounds by ring formation.

O'I'IO DALMER. CLAUS DIEHL. HARTMANN PIEPER.

DISCLAIMER 2,098,954.Ott0 Dalmer, Claus Diehl, and Hartmann Pieper,Darmstadt, Germany. HYDROURACIL COMPOUNDS AND PROCESSES FOR THEIRPRODUCTION. Patent dated November 16, 1937. Disclaimer filed April 11,1938, by the patentees; the assignee, Merck at 00., Inc, concurring.

Hereby enter this disclaimer to that part of claim 18 in saidspecification relating to processes for the conversion of urethanocompounds to hydrouracil compounds except those processes in which theurethane compounds are treated with alkaline condensing agents to obtainhydrouracils by ring formation.

[Ofiicial Gazette May 10, 1938.]

